RU2013154295A - COMPOSITIONS OF LIPID NANOPARTICLES AND METHODS FOR DELIVERY OF mRNA - Google Patents

COMPOSITIONS OF LIPID NANOPARTICLES AND METHODS FOR DELIVERY OF mRNA Download PDF

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RU2013154295A
RU2013154295A RU2013154295/15A RU2013154295A RU2013154295A RU 2013154295 A RU2013154295 A RU 2013154295A RU 2013154295/15 A RU2013154295/15 A RU 2013154295/15A RU 2013154295 A RU2013154295 A RU 2013154295A RU 2013154295 A RU2013154295 A RU 2013154295A
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cells
composition
composition according
lipid nanoparticle
mrna
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RU2013154295/15A
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Брэйдон Чарльз ГИЛД
Фрэнк ДЕРОСА
Майкл Хартлейн
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Шир Хьюман Дженетик Терапис, Инк.
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Abstract

1. Композиция, включающая (а) участок, кодирующий функциональный секретируемый полипетпид; и (б) носитель-переносчик, включающий липидную наночастицу.2. Композиция по п.1, отличающаяся тем, что мРНК кодирует фермент, который находится в аномальном дефиците у индивидуума с лизосомной болезнью накопления.3. Композиция по п.1, отличающаяся тем, что мРНК кодирует функциональный эритропоэтин или функциональный полипептид α-галактозидазу.4. Композиция по п.1, отличающаяся тем, что молекула РНК включает по меньшей мере одну модификацию, которая придает молекуле РНК стабильность.5. Композиция по п.1, отличающаяся тем, что молекула РНК включает модификацию 5′ нетранслируемого участка указанной молекулы РНК.6. Композиция по п.5, отличающаяся тем, что указанная модификация включает введение структуры Cap1.7. Композиция по п.1, отличающаяся тем, что молекула РНК включает модификацию 3′ нетранслируемого участка указанной молекулы РНК.8. Композиция по п.7, отличающаяся тем, что указанная модификация включает введение хвоста поли А.9. Композиция по п.1, отличающаяся тем, что она дополнительно включает агент для облегчения трансфера молекулы РНК во внутриклеточный компартмент клетки-мишени.10. Композиция по п.1, отличающаяся тем, что липидная наночастица включает один или несколько катионных липидов.11. Композиция по п.1, отличающаяся тем, что липидная наночастица включает один или несколько некатионных липидов.12. Композиция по п.1, отличающаяся тем, что липидная наночастица включает один или несколько ПЭГ-модифицированных липидов.13. Композиция по п.1, отличающаяся тем, что липидная наночастица включает С12-200.14. Композиция по п.1, отличающаяся1. A composition comprising (a) a plot encoding a functional secreted polypetpid; and (b) a carrier vehicle comprising a lipid nanoparticle. 2. The composition according to claim 1, characterized in that the mRNA encodes an enzyme that is in abnormal deficiency in an individual with lysosomal storage disease. The composition according to claim 1, characterized in that the mRNA encodes a functional erythropoietin or a functional α-galactosidase polypeptide. A composition according to claim 1, characterized in that the RNA molecule includes at least one modification that gives the RNA molecule stability. The composition according to claim 1, characterized in that the RNA molecule includes a modification of the 5 ′ untranslated region of the indicated RNA molecule. The composition according to claim 5, characterized in that said modification includes the introduction of the structure Cap1.7. A composition according to claim 1, characterized in that the RNA molecule comprises a modification of the 3 ′ untranslated region of the indicated RNA molecule. The composition according to claim 7, characterized in that said modification comprises the introduction of a poly A.9 tail. The composition according to claim 1, characterized in that it further comprises an agent for facilitating the transfer of the RNA molecule into the intracellular compartment of the target cell. The composition according to claim 1, wherein the lipid nanoparticle comprises one or more cationic lipids. The composition of claim 1, wherein the lipid nanoparticle comprises one or more non-cationic lipids. A composition according to claim 1, characterized in that the lipid nanoparticle comprises one or more PEG-modified lipids. The composition according to claim 1, characterized in that the lipid nanoparticle comprises C12-200.14. The composition according to claim 1, characterized

Claims (40)

1. Композиция, включающая (а) участок, кодирующий функциональный секретируемый полипетпид; и (б) носитель-переносчик, включающий липидную наночастицу.1. A composition comprising (a) a plot encoding a functional secreted polypetpid; and (b) a carrier vehicle comprising a lipid nanoparticle. 2. Композиция по п.1, отличающаяся тем, что мРНК кодирует фермент, который находится в аномальном дефиците у индивидуума с лизосомной болезнью накопления.2. The composition according to claim 1, characterized in that the mRNA encodes an enzyme that is in abnormal deficiency in an individual with lysosomal storage disease. 3. Композиция по п.1, отличающаяся тем, что мРНК кодирует функциональный эритропоэтин или функциональный полипептид α-галактозидазу.3. The composition according to claim 1, characterized in that the mRNA encodes a functional erythropoietin or a functional α-galactosidase polypeptide. 4. Композиция по п.1, отличающаяся тем, что молекула РНК включает по меньшей мере одну модификацию, которая придает молекуле РНК стабильность.4. The composition according to claim 1, characterized in that the RNA molecule includes at least one modification that gives the RNA molecule stability. 5. Композиция по п.1, отличающаяся тем, что молекула РНК включает модификацию 5′ нетранслируемого участка указанной молекулы РНК.5. The composition according to claim 1, characterized in that the RNA molecule includes a modification of 5 ′ untranslated region of the specified RNA molecule. 6. Композиция по п.5, отличающаяся тем, что указанная модификация включает введение структуры Cap1.6. The composition according to claim 5, characterized in that the modification includes the introduction of the structure of Cap1. 7. Композиция по п.1, отличающаяся тем, что молекула РНК включает модификацию 3′ нетранслируемого участка указанной молекулы РНК.7. The composition according to claim 1, characterized in that the RNA molecule includes a modification of 3 ′ untranslated region of the specified RNA molecule. 8. Композиция по п.7, отличающаяся тем, что указанная модификация включает введение хвоста поли А.8. The composition according to claim 7, characterized in that the modification includes the introduction of the tail poly A. 9. Композиция по п.1, отличающаяся тем, что она дополнительно включает агент для облегчения трансфера молекулы РНК во внутриклеточный компартмент клетки-мишени.9. The composition according to claim 1, characterized in that it further comprises an agent for facilitating the transfer of the RNA molecule into the intracellular compartment of the target cell. 10. Композиция по п.1, отличающаяся тем, что липидная наночастица включает один или несколько катионных липидов.10. The composition according to claim 1, characterized in that the lipid nanoparticle includes one or more cationic lipids. 11. Композиция по п.1, отличающаяся тем, что липидная наночастица включает один или несколько некатионных липидов.11. The composition according to claim 1, characterized in that the lipid nanoparticle includes one or more non-cationic lipids. 12. Композиция по п.1, отличающаяся тем, что липидная наночастица включает один или несколько ПЭГ-модифицированных липидов.12. The composition according to claim 1, characterized in that the lipid nanoparticle includes one or more PEG-modified lipids. 13. Композиция по п.1, отличающаяся тем, что липидная наночастица включает С12-200.13. The composition according to claim 1, characterized in that the lipid nanoparticle comprises C12-200. 14. Композиция по п.1, отличающаяся тем, что липидная наночастица включает DLinKC2DMA, CHOL, DOPE и DMG-PEG-2000.14. The composition according to claim 1, characterized in that the lipid nanoparticle includes DLinKC2DMA, CHOL, DOPE and DMG-PEG-2000. 15. Композиция по п.1, отличающаяся тем, что липидная наночастица включает С12-200, DOPE, CHOL и DMGPEG2K.15. The composition according to claim 1, characterized in that the lipid nanoparticle includes C12-200, DOPE, CHOL and DMGPEG2K. 16. Композиция по п.1, отличающаяся тем, что липидная наночастица включает расщепляемый липид.16. The composition according to claim 1, characterized in that the lipid nanoparticle includes a cleavable lipid. 17. Композиция по п.1, отличающаяся тем, что указанная композиция лиофилизирована.17. The composition according to claim 1, characterized in that the composition is lyophilized. 18. Композиция по п.1, отличающаяся тем, что указанная композиция является восстановленной лиофилизированной композицией.18. The composition according to claim 1, characterized in that said composition is a reconstituted lyophilized composition. 19. Композиция по п.10, отличающаяся тем, что указанную клетку-мишень выбирают из группы, состоящей из гепатоцитов, эпителиальных клеток, гематопоэтических клеток, эпителиальных клеток, эндотелиальных клеток, клеток легкого, клеток кости, стволовых клеток, мезенхимных клеток, нейральных клеток, сердечных клеток, адипоцитов, клеток гладкой мускулатуры сосудов, кардиомиоцитов, клеток скелетной мускулатуры, бета-клеток, питуицитов, клеток синовиальной сумки, клеток яичника, клеток яичек, фибробластов, В-клеток, Т-клеток, ретикулоцитов, лейкоцитов, гранулоцитов и опухолевых клеток.19. The composition of claim 10, wherein said target cell is selected from the group consisting of hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, lung cells, bone cells, stem cells, mesenchymal cells, neural cells , cardiac cells, adipocytes, vascular smooth muscle cells, cardiomyocytes, skeletal muscle cells, beta cells, pituititis, synovial bag cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocyte ov, granulocytes and tumor cells. 20. Способ лечения субъекта, имеющего дефицит функционального полипептида, включающий введение композиции, включающей (а) по меньшей мере одну мРНК по меньшей мере участок которой кодирует функциональный секретируемый полипептид; и (б) носитель-переносчик, включающий липидную наночастицу, при этом последующее введение указанной композиции указанной мРНК экспрессируется в клетке-мишени для получения указанного функционально секретируемого полипептида.20. A method of treating a subject having a functional polypeptide deficiency, comprising administering a composition comprising (a) at least one mRNA, at least a portion of which encodes a functional secreted polypeptide; and (b) a carrier carrier comprising a lipid nanoparticle, wherein subsequent administration of said composition of said mRNA is expressed in a target cell to obtain said functionally secreted polypeptide. 21. Способ по п.20, отличающийся тем, что мРНК кодирует функциональный эритропоэтин, α-галактозидазу, рецептор ЛНП, фактор VIII, фактор IX, α-L-идуронидазу, идуронат сульфатазу, гепарин-N-сульфатазу, α-N-ацетилглюкозаминидазу, галактозо 6-сульфатазу, β-галактозидазу, лизосомальную кислую липазу или полипептид арилсульфатазу-А; и (б) носитель-переносчик, при этом последующее введение указанной композиции указанной мРНК экспрессируется в клетке-мишени для получения указанного функционально секретируемого полипептида.21. The method according to claim 20, characterized in that the mRNA encodes functional erythropoietin, α-galactosidase, LDL receptor, factor VIII, factor IX, α-L-iduronidase, iduronate sulfatase, heparin-N-sulfatase, α-N-acetylglucosaminidase galactose 6-sulfatase, β-galactosidase, lysosomal acid lipase or arylsulfatase-A polypeptide; and (b) a carrier carrier, wherein subsequent administration of said composition of said mRNA is expressed in the target cell to produce said functionally secreted polypeptide. 22. Способ по п.20, отличающийся тем, что функционально секретируемый полипептид является ферментом, находящимся в аномальном дефиците у индивидуума с лизосомной болезнью накопления.22. The method according to claim 20, characterized in that the functionally secreted polypeptide is an enzyme in abnormal deficiency in an individual with lysosomal storage disease. 23. Способ по п.20, отличающийся тем, что молекула мРНК включает по меньшей мере одну модификацию, которая придает молекуле мРНК стабильность.23. The method according to claim 20, characterized in that the mRNA molecule includes at least one modification, which gives the mRNA molecule stability. 24. Способ по п.20, отличающийся тем, что молекула мРНК включает модификацию 5′ нетранслируемого участка указанной молекулы мРНК.24. The method according to claim 20, characterized in that the mRNA molecule includes a modification of 5 ′ untranslated region of the specified mRNA molecule. 25. Способ по п.24, отличающийся тем, что указанная модификация включает введение структуры Сар1.25. The method according to paragraph 24, wherein the specified modification includes the introduction of the structure of Sar. 26. Способ по п.20, отличающийся тем, что молекула мРНК включает модификацию 3′ нетранслируемого участка указанной молекулы мРНК.26. The method according to claim 20, characterized in that the mRNA molecule includes a modification of 3 ′ untranslated region of the specified mRNA molecule. 27. Способ по п.26, отличающийся тем, что указанная модификация включает введение хвоста поли А.27. The method according to p. 26, characterized in that the said modification includes the introduction of the tail poly A. 28. Способ по п.20, отличающийся тем, что он дополнительно включает агент для облегчения трансфера молекулы мРНК во внутриклеточный компартмент клетки-мишени.28. The method according to claim 20, characterized in that it further includes an agent for facilitating the transfer of the mRNA molecule into the intracellular compartment of the target cell. 29. Способ по п.20, отличающийся тем, что липидная наночастица включает один или несколько катионных липидов.29. The method according to claim 20, characterized in that the lipid nanoparticle comprises one or more cationic lipids. 30. Способ по п.20, отличающийся тем, что липидная наночастица включает один или несколько некатионных липидов.30. The method according to claim 20, characterized in that the lipid nanoparticle comprises one or more non-cationic lipids. 31. Способ по п.20, отличающийся тем, что липидная наночастица включает один или несколько ПЭГ-модифицированных липидов.31. The method according to claim 20, characterized in that the lipid nanoparticle includes one or more PEG-modified lipids. 32. Способ по п.20, отличающийся тем, что липидная наночастица включает С12-200.32. The method according to claim 20, characterized in that the lipid nanoparticle includes C12-200. 33. Способ по п.20, отличающийся тем, что липидная наночастица включает DLinKC2DMA, CHOL, DOPE и DMG-PEG-2000.33. The method according to claim 20, characterized in that the lipid nanoparticle includes DLinKC2DMA, CHOL, DOPE and DMG-PEG-2000. 34. Способ по п.20, отличающийся тем, что липидная наночастица включает С12-200, DOPE, CHOL и DMGPEG2K.34. The method according to claim 20, characterized in that the lipid nanoparticle includes C12-200, DOPE, CHOL and DMGPEG2K. 35. Способ по п.20, отличающийся тем, что липидная наночастица включает расщепляемый липид.35. The method according to claim 20, characterized in that the lipid nanoparticle comprises a cleavable lipid. 36. Способ по п.20, отличающийся тем, что указанная композиция лиофилизирована.36. The method according to claim 20, characterized in that the composition is lyophilized. 37. Способ по п.20, отличающийся тем, что указанная композиция является восстановленной лиофилизированной композицией.37. The method according to claim 20, characterized in that said composition is a reconstituted lyophilized composition. 38. Способ по п.20, отличающийся тем, что указанную клетку-мишень выбирают из группы, состоящей из гепатоцитов, эпителиальных клеток, гематопоэтических клеток, эпителиальных клеток, эндотелиальных клеток, клеток легкого, клеток кости, стволовых клеток, мезенхимных клеток, нейральных клеток, сердечных клеток, адипоцитов, клеток гладкой мускулатуры сосудов, кардиомиоцитов, клеток скелетной мускулатуры, бета-клеток, питуицитов, клеток синовиальной сумки, клеток яичника, клеток яичек, фибробластов, В-клеток, Т-клеток, ретикулоцитов, лейкоцитов, гранулоцитов и опухолевых клеток.38. The method according to claim 20, wherein said target cell is selected from the group consisting of hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, lung cells, bone cells, stem cells, mesenchymal cells, neural cells , cardiac cells, adipocytes, vascular smooth muscle cells, cardiomyocytes, skeletal muscle cells, beta cells, pituititis, synovial bag cells, ovarian cells, testicular cells, fibroblasts, B cells, T cells, reticulocytes, leukocytes, g ranulocytes and tumor cells. 39. Способ лечения субъекта, имеющего дефицит функционального секретируемого полипептида, включающий введение композиции, включающей (а) по меньшей мере одну мРНК по меньшей мере участок которой кодирует функциональный секретируемый полипептид; и (б) носитель-переносчик, включающий липидную наночастицу, при этом последующее введение указанной композиции указанной мРНК транслируется в клетку-мишень для получения функционального полипептида в указанной клетке-мишени по меньшей мере при минимальном терапевтическом уровне более чем спустя один час после введения.39. A method of treating a subject having a deficiency of a functional secreted polypeptide, comprising administering a composition comprising (a) at least one mRNA, at least a portion of which encodes a functional secreted polypeptide; and (b) a carrier carrier comprising a lipid nanoparticle, wherein subsequent administration of said composition of said mRNA is translated into a target cell to obtain a functional polypeptide in said target cell at least at a minimum therapeutic level more than one hour after administration. 40. Способ получения функционального секретируемого полипептида в клетке-мишени, включающий введение композиции, включающей (а) по меньшей мере одну мРНК по меньшей мере участок которой кодирует функциональный секретируемый полипептид; и (б) носитель-переносчик, включающий липидную наночастицу, при этом последующее введение указанной композиции указанной мРНК транслируется в клетку-мишень для получения функционального секретируемого полипептида по меньшей мере при минимальном терапевтическом уровне более чем спустя один час после введения. 40. A method for producing a functional secreted polypeptide in a target cell, comprising administering a composition comprising (a) at least one mRNA, at least a portion of which encodes a functional secreted polypeptide; and (b) a carrier carrier comprising a lipid nanoparticle, wherein subsequent administration of said composition of said mRNA is transmitted to the target cell to obtain a functional secreted polypeptide at least at the minimum therapeutic level more than one hour after administration.
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